1. Sumoylation by Ubc9 Regulates the Stem Cell Compartment and Structure and Function of the Intestinal Epithelium in Mice
- Author
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Esther Danenberg, Alexandra Andrieux, Karim Nacerddine, Ana Cumano, Ghislaine Hamard, Perrine Bomme, Grégory Jouvion, Anne Dejean, Béatrice Romagnolo, Maud D. Demarque, Nick Barker, Hélène Neyret–Kahn, Hans Clevers, Benoit Terris, Hubrecht Institute for Developmental Biology and Stem Cell Research, Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Histotechnologie et Pathologie, Institut Pasteur [Paris], Microscopie Ultrastructurale (Plate-forme), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service d'Anatomie Pathologique, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Développement des Lymphocytes, Organisation Nucléaire et Oncogenèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] ( PRHTEC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Cochin [AP-HP], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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SUMO protein ,MESH : Tamoxifen ,MESH: Mice, Knockout ,Mice ,0302 clinical medicine ,Keratin ,[ SDV.IMM ] Life Sciences [q-bio]/Immunology ,MESH: Animals ,Intestinal Mucosa ,health care economics and organizations ,chemistry.chemical_classification ,Mice, Knockout ,0303 health sciences ,Stem Cells ,MESH: Sumoylation ,Gastroenterology ,LGR5 ,MESH : Sumoylation ,Intestinal epithelium ,Cell biology ,MESH : Phenotype ,medicine.anatomical_structure ,Phenotype ,Biochemistry ,MESH : Stem Cells ,MESH: Intestinal Mucosa ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Basal lamina ,Stem cell ,MESH : Ubiquitin-Conjugating Enzymes ,education ,MESH: Stem Cells ,Biology ,MESH: Phenotype ,MESH : Intestinal Mucosa ,03 medical and health sciences ,MESH : Mice ,medicine ,Animals ,MESH: Mice ,030304 developmental biology ,Hepatology ,Sumoylation ,Small intestine ,MESH: Ubiquitin-Conjugating Enzymes ,Tamoxifen ,chemistry ,Ubiquitin-Conjugating Enzymes ,Keratin 8 ,MESH : Mice, Knockout ,MESH: Tamoxifen ,MESH : Animals ,030217 neurology & neurosurgery - Abstract
Background & Aims Small ubiquitin-like modifiers (SUMOs) are attached to other proteins to regulate their function (sumoylation). We investigated the role of Ubc9, which covalently attaches SUMOs to proteins, in the gastrointestinal tract of adult mice. Methods We investigated the effects of decreased sumoylation in adult mammals by generating mice with an inducible knockout (by injection of 4-hydroxytamoxifen) of the E2 enzyme Ubc9 ( Ubc9fl/-/ROSA26-CreERT2 mice). We analyzed the phenotypes using a range of histologic techniques. Results Loss of Ubc9 from adult mice primarily affected the small intestine. Ubc9fl/−/ROSA26-CreERT2 mice died within 6 days of 4-hydroxytamoxifen injection, losing 20% or less of their body weight and developing severe diarrhea on the second day after injection. Surprisingly, other epithelial tissues appeared to be unaffected at that stage. Decreased sumoylation led to the depletion of the intestinal proliferative compartment and to the rapid disappearance of stem cells. Sumoylation was required to separate the proliferative and differentiated compartments from the crypt and control differentiation and function of the secretory lineage. Sumoylation was required for nucleus positioning and polarized organization of actin in the enterocytes. Loss of sumoylation caused detachment of the enterocytes from the basal lamina, as observed in tissue fragility diseases. We identified the intermediate filament keratin 8 as a SUMO substrate in epithelial cells. Conclusions Sumoylation maintains intestinal stem cells and the architecture, mechanical stability, and function of the intestinal epithelium of mice.
- Published
- 2010
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